This invention relates to benzocycloalkylenylamine derivatives, associated pharmaceutically acceptable salts, or hydrates thereof, and associated pharmaceutical compositions and methods for use as M2/M3 selective muscarinic receptor antagonists.
Acetylcholine (Ach) is the principal transmitter of the parasympathetic nervous system. The physiological actions of Ach are mediated by activation of either nicotinic or muscarinic receptors. Both of these receptor classes are heterogeneous: e.g., the muscarinic receptor family comprises five subtypes (M1, M2, M3, M4, and M5) each encoded by distinct genes and possessing unique pharmacology and distribution.
Almost all smooth muscle tissues express both muscarinic M2 and M3 receptors, both of which have a functional role. M2 receptors outnumber M3 receptors by a proportion of approximately 4 to 1. Generally, M3 receptors mediate the direct contractile effects of acetylcholine in the vast majority of smooth muscle tissues. M2 receptors, on the other hand, cause smooth muscle contraction indirectly by inhibiting sympathetically (xcex2-adrenoreceptor)-mediated relaxation.
Compounds that act as antagonists of muscarinic receptors have been used to treat several disease states associated with improper smooth muscle function. Until recently, most of these compounds have been non-selective for the various muscarinic receptor subtypes, leading to unpleasant anti-cholinergic side-effects such as dry mouth, constipation, blurred vision, or tachycardia. The most common of these side-effects is dry-mouth resulting from muscarinic receptor blockade in the salivary gland. Recently developed M2 or M3 specific antagonists have been shown to have reduced side effects. Evidence suggests that concurrent blockade of M2 and M3 receptors could be therapeutically effective in the treatment of disease states associated with smooth muscle disorders.
Few M2/M3 selective antagonists have been developed. The present invention fills this need by providing these types of antagonists useful in the treatment of disease states associated with improper smooth muscle function.
This invention relates to compounds comprising Formula I: 
wherein:
R1, and R2 are independently in each occurrence hydrogen, halogen, (C1-6)-alkyl, xe2x80x94ORxe2x80x2, xe2x80x94SRxe2x80x2, xe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94SORxe2x80x2, xe2x80x94SO2Rxe2x80x2, xe2x80x94COORxe2x80x2, xe2x80x94OCORxe2x80x2, xe2x80x94OCONRxe2x80x2Rxe2x80x3, xe2x80x94OCONRxe2x80x2Rxe2x80x3, xe2x80x94OSO2Rxe2x80x2, xe2x80x94OSO2NRxe2x80x2Rxe2x80x3; xe2x80x94NRxe2x80x2SO2Rxe2x80x3, xe2x80x94NRxe2x80x2CORxe2x80x3, xe2x80x94SO2NRxe2x80x2Rxe2x80x3, xe2x80x94SO2(CH2)1-3CONRxe2x80x2Rxe2x80x3, xe2x80x94CONRxe2x80x2Rxe2x80x3, xe2x80x94NRxe2x80x2CONRxe2x80x2Rxe2x80x3, cyano, haloalkyl, or nitro;
Rxe2x80x2 and Rxe2x80x3 are independently in each occurrence hydrogen, (C1-6)-alkyl, haloalkyl, aryl, heterocyclyl, heteroaryl, aryl-(C1-3)-alkyl, heteroaryl-(C1-3)-alkyl, heterocyclyl-(C1-3)-alkyl, cycloalkylalkyl, cycloalkyl, or Rxe2x80x2 and Rxe2x80x3 together with the nitrogen they are attached may also form a 5- to 7-membered ring, optionally incorporating one additional ring heteroatom chosen from N, O or S(O)0-2;
R3 is independently in each occurrence (C1-6) alkyl, (C1-6) alkenyl, (C1-6) alkynyl, or cycloalkyl;
one of X, Y or Z is independently S, O, or Nxe2x80x94R4, the others are CH2;
R4 is hydrogen, (C1-6)-alkyl, haloalkyl, aryl(C1-6)alkyl, heteroaryl(C1-6)alkyl, xe2x80x94(C1-6)xe2x80x94CRxe2x80x2Rxe2x80x2Rxe2x80x2, xe2x80x94COORxe2x80x2, xe2x80x94SO2Rxe2x80x2, xe2x80x94C(O)Rxe2x80x2, xe2x80x94SO2(CH2)0-3NRxe2x80x2Rxe2x80x3, xe2x80x94CONRxe2x80x2Rxe2x80x3, or xe2x80x94PO(ORxe2x80x2)2, where Rxe2x80x2 and Rxe2x80x3 are as defined above;
m is an integer from 0 to 3 inclusive;
n is an integer from 1 to 6 inclusive;
p is an integer from 1 to 3 inclusive; and prodrugs, individual isomers, racemic or non-racemic mixtures of isomers, and pharmaceutically acceptable salts or solvates thereof.
In a preferred embodiment p is 2.
In another preferred embodiment p is 2, and one of X, Y or Z is NR4 and the others are CH2; in another embodiment p is 2, and one of X, Y or Z is NR4 and the others are CH2, wherein R4 is hydrogen.
In another preferred embodiment, p is 2 and m is 1; in another preferred embodiment p is 2, m is 1 and Y is NR4 and the others are CH2 and in another preferred embodiment p is 2, m is 1 and one of X is NH and the others are CH2; In another preferred embodiment, p is 2, m is 2; in another preferred embodiment, p is 2, m is 2, and one of X, Y or Z is NR4 and the others are CH2, and in another preferred embodiment p is 2, m is 2, and one of X is NH and the others are CH2.
In another embodiment n is 3 and p is 2, in another embodiment n is 3, and one of X, Y or Z is NR4 and the others are CH2; in another embodiment n is 3, p is 2 and one of X, Y, or Z is NR4 and the others are CH2 in another embodiment n is 3, p is 2 and one of X, Y, or Z is NH and the others are CH2. In another preferred embodiment n is 3, p is 2, m is 2 and one of X, Y, or Z is NR4 and the others are CH2; and in another preferred embodiment n is 3, p is 2, m is 2, X is NH, and Y and Z are CH2. In another preferred embodiment n is 3, p is 2, m is 2, Y is NH and X and Z are CH2. In another preferred embodiment n is 3, p is 2, m is 2, Z is NH and X and Y are CH2.
In another embodiment n is 3 and one of X, Y, or Z is NR4 and the others are CH2.
In another preferred embodiment p is 2, m is 2, n is 3, one of X, Y or Z is O and the others are CH2.
In a preferred embodiment, the invention further relates to pharmaceutical compositions containing a therapeutically effective amount of at least one compound of Formula I, or prodrugs, individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof, in admixture with at least one suitable carrier. In a more preferred embodiment, the pharmaceutical compositions are suitable for administration to a subject having a disease state which is alleviated by treatment with a muscarinic M2/M3 receptor antagonist.
In another aspect, the invention relates to methods for treating a subject having a disease state that is alleviated by treatment with a muscarinic M2/M3 receptor antagonist, which comprises administering to such a subject a therapeutically effective amount of at least a compound of Formula I. In a preferred embodiment, the subject has a disease state comprising smooth muscle disorders; preferably genitourinary tract disorders, respiratory tract disorders, gastrointestinal tract disorders; more preferably genitourinary tract disorders such as overactive bladder or detrusor hyperactivity and its symptoms, such as the changes symptomatically manifested as urgency, frequency, reduced bladder capacity, incontinence episodes, and the like; the changes urodynamically manifested as changes in bladder capacity, micturition threshold, unstable bladder contractions, sphincteric spasticity, and the like; and the symptoms usually manifested in detrusor hyperreflexia (neurogenic bladder), in conditions such as outlet obstruction, outlet insufficency, pelvic hypersensitivity, or in idiopathic conditions such as detrusor instability, and the like. In another preferred embodiment, the disease comprises respiratory tract disorders such as allergies and asthma. In another preferred embodiment, the disease state comprises gastrointestinal disorders.
In another aspect, the invention relates to a process for preparing a compound of Formula I, which process comprises reacting a compound having a general formula 
with a compound of general formula 
to provide a compound of Formula I: 